Military personnel are frequently exposed to blast-induced shock waves (acoustic blast overpressure, ABO), with intensities sufficient to cause polytrauma, of which traumatic brain injury (TBI) is a common component. Relatively little is known about the structural or functional effects on the retina per se induced by ABO exposure, which initially may be occult and not manifest significantly until weeks to months post-blast. This project focuses on providing an understanding of the etiology and treatment o f ABO-associated retinal and visual system defects, as well as attendant CNS and motor system damage and dysfunction. Prior studies have implicated oxidative stress in the pathophysiology of ABO-induced polytrauma, suggesting that antioxidants may provide an effective therapeutic intervention against such injury. In addition, neuroprotective agents have shown promise for intervening in TBI, using a rat model employing direct mechanical impact to the brain (i.e., the ?lateral fluid percussion? (LFP) model). Herein, we directly compare our rat ABO model of primary blast injury against the complimentary LFP TBI model, and show ?molecular signature? linking the two models, suggesting common underlying mechanisms for the observed pathologies in both. Using both models, we will test the efficacy of a novel, blood-brain- barrier permeable multifunctional antioxidant (MFAO (?HK-2?)) and a neuroprotectant (phenoxybenzamine (?PBZ?)), alone and in combination, to limit the severity of polytrauma. AIM 1 will evaluate the therapeutic efficacy of HK-2 and PBZ in preventing or attenuating ABO-induced polytrauma (visual, cognitive and neuromotor deficits, and CNS structural abnormalities). In an analogous manner, AIM 2 will evaluate the therapeutic efficacy of HK-2 and PBZ in preventing or attenuating LFP-induced polytrauma. State-of-the-art methods for assessing visual, cognitive, and neuromotor function, as well as retina and brain structure, will be employed, along with correlative biochemical, immunological, and histological methodologies. Relevance to Active Military and Veterans' Healthcare Issues: TBI is the signature injury of the conflicts in Iraq and Afghanistan (OEF/OIF). Currently, there are no effective treatments or prophylactic interventions to minimize or prevent ABO-induced polytrauma, including TBI and attendant vision deficits. With thousands of active military personnel being subjected to such injury- provoking conditions on a recurrent basis, this presents a significant unresolved healthcare issue for active military personnel and Veterans. PIs and Environment: The Site 1 PI (Fliesler) has a >35-year record of productivity in eye/vision research, involving animal models of retinal degenerations and employing a diversity of molecular/cell biological methodologies. He is Director of the Vision Research Center and a Research Career Scientist Award (RCSA) recipient at the Buffalo VAMC, and an endowed chair Professor/Vice-Chair/Research Director in the Dept. of Ophthalmology at the University at Buffalo (UB). He has the ABO rat model and HK-2 in-house. A UB collaborator (Poulsen) has the LFP model established in his lab, has utilized the rat LFP TBI model for >15 years, and has investigated multiple neuroprotective agents using this model. He is a Professor of Translational Neuroscience and a member of the Neurosurgery Department, and has extensive experience in both functional behavior and cognitive assessments relative to the rat TBI model. The Site 2 PI (Pardue) is a RCSA recipient at the Atlanta VAMC, Assoc. Director of Scientific Projects at the Atlanta VA Rehab R&D Center of Excellence, and Professor of Biomedical Engineering at Georgia Institute of Technology, with >25 years of experience in eye/vision research, particularly as involves electrophysiological and behavioral diagnostic methods. The PIs have an established and ongoing collaborative relationship, and have superlative resources and supportive environments to ensure the successful execution of this project.